Targeted Alpha Therapy of Glioma Using ²¹¹At-Labeled Heterodimeric Peptide Targeting Both VEGFR and Integrins

Targeted radionuclide therapy based on α-emitters plays an increasingly important role in cancer treatment. In this study, we proposed to apply a heterodimeric peptide (iRGD-C6-lys-C6-^DA7R) targeting both VEGFR and integrins as a new vector for ²¹¹At radiolabeling to obtain high-performance radiopharmaceuticals with potential in targeted alpha therapy (TAT). An astatinated peptide, iRGD-C6-lys(²¹¹At-ATE)-C6-^DA7R, was prepared with a radiochemical yield of ∼45% and high radiochemical purity of >95% via an electrophilic radioastatodestannylation reaction. iRGD-C6-lys(²¹¹At-ATE)-C6-^DA7R showed good stability in vitro and high binding ability to U87MG (glioma) cells. Systematic in vitro antitumor investigations involving cytotoxicity, apoptosis, distribution of the cell cycle, and reactive oxygen species (ROS) clearly demonstrated that ²¹¹At-labeled heterodimeric peptides could significantly inhibit cell viability, induce cell apoptosis, arrest the cell cycle in G2/M phase, and increase intracellular ROS levels in a dose-dependent manner. Biodistribution revealed that iRGD-C6-lys(²¹¹At-ATE)-C6-^DA7R had rapid tumor accumulation and fast normal tissue/organ clearance, which was mainly excreted through the kidneys. Moreover, in vivo therapeutic evaluation indicated that iRGD-C6-lys(²¹¹At-ATE)-C6-^DA7R was able to obviously inhibit tumor growth and prolong the survival of mice bearing glioma xenografts without notable toxicity to normal organs. All these results suggest that TAT mediated by iRGD-C6-lys(²¹¹At-ATE)-C6-^DA7R can provide an effective and promising strategy for the treatment of glioma and some other tumors.